Cigarette smoking is a worldwide epidemic and the most prevalent cause of many diseases leading to increased morbidity and mortality globally. The impact of smoking on pathogenesis of cancer is being extensively studied however cigarette smoke as an immunosuppressant is less well recognized. Here we review the immunosuppressive effects of cigarette smoke and the mechanisms by which smoking affects host innate immunity including structural and functional changes in the respiratory ciliary epithelium, lung surfactant protein, and immune cells such as alveolar macrophages, neutrophils, lymphocytes and natural killer (NK) cells. Thus smoking cessation should be emphasized not only for prevention of cancer and coronary artery disease but also for patients with recurrent infections and immunosuppressive states.